An Efficient Synthesis of 4-Arylmethylidene-3-substituted-Isoxazol-5(4H)-ones in Aqueous Medium

Article abstract of DOI:10.1002/jhet.2293

A series of 4-arylmethylidene-3-substituted-isoxazol-5(4H)-ones were efficiently synthesized by eco-benign, one pot uncatalyzed reaction of β-keto-ester, hydroxylamine hydrochloride, and aromatic aldehyde with electron donating substituent in water.

Full text of DOI:10.1002/jhet.2293

Month 2014
An Efficient Synthesis of 4-Arylmethylidene-3-substituted-Isoxazol-
5(4H)-ones in Aqueous Medium
a
a
a
*
Abhijit P. Chavan, Avinash B. Pinjari, and Pravin C. Mhaske
Post Graduate Department of Chemistry, Sir Parashurambahu College, Tilak Road, (Affiliated to University of Pune),
Pune 411 030, India
*
E-mail: mhaskepc18@gmail.com
Received March 12, 2014
DOI 10.1002/jhet.2293
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A series of 4-arylmethylidene-3-substituted-isoxazol-5(4H)-ones were efficiently synthesized by eco-
benign, one pot uncatalyzed reaction of β-keto-ester, hydroxylamine hydrochloride, and aromatic aldehyde
with electron donating substituent in water.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
benign method for the synthesis of 4-arylmethylidene-3-
substituted-isoxazol-5(4H)-one derivatives. Thus, the syn-
thesis of 4-arylmethylidene-3-methyl-isoxazol-5(4H)-one
was attempted using equimolecular quantities of β-keto-
esters, hydroxylamine hydrochloride, and an aromatic
aldehyde in an aqueous medium (Scheme 1).
Increased environmental awareness within the synthetic
chemistry community has lately pushed green chemistry
technologies to the fore. Since the last decade, the develop-
ment of non-hazardous alternatives is not only due to the
increased regulatory pressure focusing on organic solvents
but also for sustainability benefits. Viewed in this light,
water is uniquely advantageous as a solvent [1–10].
RESULTS AND DISCUSSION
Isoxazolone is a class of heterocyclic compounds having
a remarkable number of pharmaceutical [11–14] applica-
tions and have been demonstrated to be versatile building
blocks in the synthesis of natural products [15–18], in op-
tical recording, and nonlinear optical research [19,20].
4-(Arylmethylene)-isoxazol-5-ones are known to be useful
building blocks for the preparation of fused heterocycles
[21–24]. The synthesis of 4-arylmethylidene-3-methyl-
isoxazol-5(4H)-one derivatives involves a coupling of
ethyl acetoacetate, hydroxylamine hydrochloride, and aro-
matic aldehydes catalyzed in basic medium [25,26]. Liter-
ature enumerates different reagents, catalysts, and/or
reaction medium viz pyridine [27], sodium benzoate [28],
sodium silicate [29], sodium sulfide [30], sodium ascorbate
[31], sodium tartraborate [32], boric acid [33], sodium
azide [34], sodium saccharin [35], and sodium citrate
[36] in the presence of organic solvents and/or water. Liter-
ature also revealed that the methods indicated previously
requires high temperature [37], long reaction time
[37,38], reagent in stoichiometric amount [27,38], and the
reaction conditions like grinding or use of ultrasound irra-
diation [38], or visible light [39]. Recently, we have re-
ported [40–42] the synthesis of β-hydroxyester, 4-aryl/
alkylaminocoumarins under solvent-free condition using
microwave irradiation and synthesis of xanthene derivatives
in aqueous medium. The success of these reactions encouraged
us to probe the development of efficient and environmentally
In the beginning, the synthesis of 4-(4-methoxyphenyl)-
3-methyl-5(4H)-isoxazolone (4a) was carried out by
reacting ethyl 3-oxobutanoate, 1a and hydroxylamine hy-
drochloride (2), and 4-methoxybenzaldehyde (3a) in water.
It was observed that the reaction proceeded effectively
without any catalyst in 91% yield (Scheme 2).
It is known that the Knöevenagel type reactions are
solvent-dependent and that usually dipolar aprotic sol-
vents, like DMF, are especially useful in this condensation.
This is because the second step, viz 1,2-elimination, is
inhibited by protic solvents [25]. The effects of various sol-
vents with different properties, like polarity and proticity,
were employed in the model reaction (Scheme 2) to opti-
mize the reaction conditions. The representative results
are summarized in Table 1, which showed that the reaction
works well in water (Table 1, entry 7).
The Knöevenagel condensation reaction proceeds
smoothly in water to afford the desired product 4a in
91% yield (Table 1, entry 7). The enhanced reactivity in
aqueous medium observed in some reactions was rational-
ized by various researchers [5] as a consequence of hydro-
phobic effects and enforced hydrophobic interactions. The
protic solvents are favorable over the usual DMSO or
DMF, which are toxic, teratogenic, and suspected carcino-
genic solvents. Further, this model reaction occurs with
moderate yield in ethanol (81%), methanol (79%), and
isopropanol (74%) (Table 1, entries 4–6, respectively).
© 2014 HeteroCorporation

A. P. Chavan, A. B. Pinjari, and P. C. Mhaske
Vol 000
Scheme 1. Synthesis of 4-arylmethylidene-3-methyl-isoxazol-5(4H)-one.
Scheme 2. Synthesis of 4-(4-methoxyphenyl)-3-methyl-5(4H)-isoxazolone (4a).
Table 1
Solvent effect on the yield of model reaction (Scheme 2).
Table 2
Synthesis of 4-arylmethylidene-3-methyl-isoxazol-5(4H)-one in
aqueous medium.
Entry
Solventa
Yieldb (%)
1
2
3
4
5
6
7
None
DMF
DMSO
EtOH
MeOH
IPA
20
88
75
81
79
74
91
H2O
R = CH3
R = C2H5
aThe reaction was carried out in solvents (5 mL) for 2 h.
bIsolated yield.
Product
Ar
Time
Yielda
(%)
Time Yielda
(min)
(min)
(%)
The moderate yields were obtained in alcoholic medium
that suggest the hydrophobic effect of polar protic solvents.
Because the reaction easily occurs in non-basic aqueous
medium, glass catalyzed processes were excluded by carry-
ing out the reaction in a polyethylene vessel, which gave
85% yields.
The investigation was further extended by substituting
ethyl 3-oxobutanoate with methyl 3-oxobutanoate, and it
was observed that the yield of the product was increased
up to 17%. This may be due to the easier substitution of
–OCH3 group of methyl 3-oxobutanoate compared to –
OC2H5 group of ethyl 3-oxobutanoate (Table 2).
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4 H3CO-Ph
2 H3CO-Ph
4 H5C2O-Ph
3,4 OCH2O Ph
2 HO-Ph
3 HO-Ph
4 HO-Ph
4 Me2N-Ph
4 H3C-Ph
3-F-Ph
30
45
30
30
75
45
20
30
60
30
20
30
30
30
97
77
90
88
70
79
90
95
80
90
98
80
90
92
30
45
30
30
75
75
20
30
60
30
20
55
30
30
88
60
85
82
45
60
88
84
75
80
90
72
86
73
4-F-Ph
Ph
Ph-CH = CH-
3-Indole
aIsolated yield.
It was found that aldehydes having a wide range of sub-
stituents undergo MCP to afford the desired product in
good yield (Table 2). The reaction of aromatic aldehydes
bearing electron donating groups at para (Table 2, com-
pounds 4a, 4c, 4d, 4g,4h, 4i, and 4k) and meta (Table 2,
compounds 4f and 4j) position provided a higher yield,
while an electron donating group at ortho (Table 2, com-
pounds 4b and 4e) resulted in lower yield. It is important
to note that α, β unsaturated aldehyde and heterocyclic al-
dehyde (Table 2, compounds 4m and 4n) underwent reac-
tion gave good yields of the corresponding products under
the same reaction condition. However, aromatic aldehydes
with an electron-withdrawing group like chloride, nitro,
failed to give the desired product.
Finally, the method was scaled up to generate multigram
quantities of 4-arylmethylidene-3-methyl-isoxazol-5(4H)-
one without any significant loss in yields. Isoxazolone de-
rivatives constitute an important and privileged structural
motif in the context of medicinal chemistry applications
[43–47]. In order to access these valuable isoxazolone
derivatives, we have evaluated the reaction of ethyl 4-
chloro-3-oxobutanoate (1b) with substituted aldehydes
and hydroxylamine hydrochloride under aqueous condi-
tion. The reactions afforded a number of 3-chloromethyl-
5(4H)-isoxazolone in excellent yields under the optimal
reaction conditions (Table 3).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Efficient Synthesis of 4-Arylmethylidene-3-substituted-Isoxazol-5(4H)-ones in
Aqueous Medium
Table 3
product was formed immediately. The resulting three-
component mixture was further stirred till completion of the
reaction (monitored by TLC). The solid material was filtered,
and washed with water (2 × 5 mL) to furnish pure product 4a–n.
If necessary, the products were further purified by crystallization
from aqueous ethanol. The same procedure was applied for the
synthesis of 4a–n and 5a–l using methyl 3-oxobutanoate (1b)
and ethyl 4-chloro-3-oxobutanoate (1c), respectively. The
Synthesis of 4-arylmethylidene-3-chloromethylene-isoxazol-5(4H)-one in
aqueous medium.
1
practical yield is presented in Tables 2 and 3. The H and 13C
NMR data of the known compounds are in good agreement
with those reported in the literature. H, 13C NMR, and HRMS
data for only new products are given in what follows, while the
spectral data for known products matched with the previously
reported literature data [25–36].
1
Product
Ar
Time (min)
Yielda (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
4 H3CO-Ph
4 H5C2O-Ph
3 HO-Ph
40
40
45
30
30
30
30
45
50
40
50
50
92
90
85
88
90
88
90
79
80
90
75
85
4-(4-Ethoxybenzylidene)-3-methyl-isoxazol-5(4H)-one (Table 2,
entry 4c).
mp 150–152 °C; IR (KBr) 1735, 1586, 1564,
4 HO-Ph
1518,1432, 1265,890 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 2.33
3,4 OCH2O-Ph
3 H3CO,4 OH-Ph
4 Me2N-Ph
4 H3CCOHN-Ph
4 H3C-Ph
(t, J= 7.2 Hz, 3H, H3C-CH2), 2.28 (s, 3H, H3C-isoxazol), 4.16
(q, J= 7.2 Hz, 2H, H3C-CH2-O), 6.70 (d, J= 8.6 Hz, 2H, Ar-H),
7.34 (s, 1H, ¼CH), 8.44 (d, J= 8.6 Hz, 2H, Ar-H); 13C NMR
(75 MHz, CDCl3) δ 14.8, 22.1, 64.7, 118.2, 129.8, 129.9, 134.2,
145.8, 150.2, 161.4, 168.3; HRMS (m/z): 232.0961 (M + H)+.
4-(3-Fluorobenzylidene)-3-methyl-isoxazol-5(4H)-one (Table 2,
5j
5k
5l
Ph
Ph-CH = CH-
3-Indole
entry 4j).
mp 142–144 °C; IR (KBr) 1730, 1686, 1594, 1520,
1427, 1250, 870 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H,
H3C-isoxazol), 7.19 (m, 1H, Ar-H), 7.32 (t, J= 7.6 Hz, 1H, Ar-H),
7.60 (m, 1H, Ar-H), 7.39 (s, 1H, ¼CH), 9.00 (m, 1H, Ar-H); 13C
NMR (75 MHz, CDCl3) δ 22.1, 111.3, 114.7, 122.2, 125.0, 132.0,
137.8, 150.9, 162.2, 165.9, 170.0; HRMS (m/z): 206.0617 (M + H)+.
4-(4-Methoxybenzylidene)-3-(chloromethyl)isoxazol-5(4H)-
aIsolated yield.
CONCLUSIONS
We have demonstrated a convenient, practical, and an
efficient method for the synthesis of 4-arylmethylidene-3-
substituted-isoxazol-5(4H)-ones in aqueous medium. This
operationally simple procedure is less laborious and pro-
vides a better scope and chemo-selectivity than previously
reported procedures.
one (Table 3, entry 5a).
mp 138–140 °C; IR (KBr) 1751,
1
1550, 1455, 1423, 1181, 1084, 922 cmꢀ1; H NMR (300 MHz,
CDCl3) δ 3.94 (s, 3H, H3C-O) 4.55 (s, 2H, Cl-CH2-isoxazol)
7.04 (d, J = 8.7 Hz, 2H, Ar-H), 7.68 (S, 1H, ¼CH), 8.49
(d, J = 8.7 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCL3) δ 35.2,
55.8, 112.5, 114.8, 125.6, 137.5, 151.1, 160.3, 165.2, 168.2;
HRMS (m/z): 252.0439 (M + H)+.
4-(4-Ethoxybenzylidene)-3-(chloromethyl)isoxazol-5(4H)-
one (Table 3, entry 5b). mp 150–152 °C IR (KBr) 1749, 1555,
1
1461, 1427, 1177, 1085, 928 cmꢀ1; H NMR (300 MHz, CDCl3)
EXPERIMENTAL
δ 1.45 (t, J = 7.2 Hz, 3H, H3C-CH2), 4.16 (q, J = 7.2 Hz, 2H,
H3C-CH2-O), 4.52 (s, 2H, Cl-CH2-isoxazol) 7.02 (d, J = 8.7 Hz,
2H, Ar-H), 7.70 (s, 1H, ¼CH), 8.50 (d, J = 8.7 Hz, 2H, Ar-H);
13C NMR (75 MHz, CDCL3) δ 17.9, 35.3, 57.8, 114.3, 115.7,
125.5, 137.8, 151.2, 160.1, 165.0, 168.0; HRMS (m/z): 232.0961
(M+ H)+.
All common reagents and solvents were used and obtained from
commercial supplies without further purification. All reactions were
monitored, and purity of the products was checked by TLC. TLC
was performed on Merck 60 F-254 (India) silica gel plates with
visualization by UV-light. Melting points were determined in
capillary tubes in silicon oil bath using a Veego melting point appa-
ratus (MP-DS, India) and are uncorrected. 1H NMR and 13C NMR
spectra were recorded on Varian mercury XL-300 (California, USA)
or Bruker spectrometer (Switzerland) instruments. Chemical shifts
are reported from internal tetramethyl silane as a standard and
are given in δ units. Infrared spectra were taken on Shimadzu
FTIR – 408 (Singapore) in KBr. Electron impact HR mass
spectra were obtained using Q-Tof Micromass mass spectrometer
(Waters, UK) using an ionizing voltage of 70 eV.
4-(3-Hydroxybenzylidene)-3-(chloromethyl)isoxazol-5(4H)-
one (Table 3, entry 5c).
mp 188–190 °C; 1H NMR
(300 MHz, DMSO-d6) δ 4.80 (s, 2H, -CH2-isoxazol), 7.06
(dd, J = 7.6 and 1.72 Hz, 1H, Ar-H), 7.39 (t, J = 8.0 Hz, 1H,
Ar-H), 7.79 (d, J = 7.6 Hz, 1H, Ar-H), 7.86 (s, 1H, ¼CH),
8.01 (s, 1H, Ar-H), 9.90 (bs, 1H, Ar-OH). 13C NMR (75 MHz,
DMSO-d6) δ 35.0, 112.2, 115.2, 119.0, 125.5, 130.8, 136.6,
152.4, 157.6, 165.2, 169.0; HRMS (m/z): 238.0266 (M + H)+.
4-(4-Hydroxybenzylidene)-3-(chloromethyl)isoxazol-5(4H)-
General procedure 4-arylmethylidene-3-methyl-isoxazol-
one (Table 3, entry 5d).
mp 190–192 °C; IR (KBr)
3159,1746,1552,1446, 1258,1176,1084,933 cmꢀ1
;
1H NMR
5(4H)-one (4a–n and 5a–l).
A mixture of ethyl 3-
oxobutanoate (1a, 0.25 g, 1.92 mmol) and hydroxylamine
hydrochloride (2, 0.13 g, 1.92 mmol) in water (5 mL) was stirred
in ice bath (5 °C) for 15 min. After the color of the mixture
changed to pale yellow, the aromatic aldehyde (3a–n,
1.92 mmol) was slowly added to the reaction mixture; the solid
(300 MHz, DMSO-d6) δ 4.88 (s, 2H, Cl-CH2-isoxazol), 7.00
(d, J = 9.1 Hz, 2H, Ar-H), 8.02 (s, 1H, ¼CH), 8.46
(d, J = 9.1 Hz, 2H, Ar-H); 11.26 (bs, 1H, Ar-OH). 13C NMR
(75 MHz, CDCl3) δ 35.3, 111.5, 113.8, 126.7, 138.9, 151.0,
161.6, 163.9, 169.5; HRMS (m/z): 238.0285 (M + H)+.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. P. Chavan, A. B. Pinjari, and P. C. Mhaske
Vol 000
4-((Benzo[d][1,3]dioxol-5-yl)methylene)-3-(chloromethyl)
isoxazol-5(4H)-one (Table 3, entry 5e). mp 184–186 °C; IR
Ar-H), 7.62–7.65 (m, 1H, Ar-H), 8.14–8.17 (m, 1H, Ar-H), 8.46
(s, 1H, ¼CH), 9.56 (d, J = 3.0 Hz, 1H, indole-H), 13.03 (bs, 1H,
HN–); 13C NMR (75 MHz, DMSO-d6) δ 35.5, 108.3, 112.3,
112.7, 118.4, 122.1, 123.5, 127.5, 135.9, 138.0, 140.0, 161.2,
169.9; HRMS (m/z): 261.0447 (M+ H)+.
(KBr) 1730, 1589, 1530, 1429, 1220, 1102, 878 cmꢀ1; H NMR
(400MHz, DMSO-d6) δ 4.84 (s, 2H, Cl-CH2-isoxazol), 6.22
(s, 2H, O-CH2-O), 7.14 (d, J = 8.2 Hz, 1H, Ar-H), 7.87
(dd, J = 8.32 and 1.72Hz, 1H, Ar-H), 8.02 (s, 1H, ¼CH), 8.40
(d, J = 1.72Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ
34.9, 102.8, 108.9, 111.4, 112.1, 127.2, 134.3, 148.0, 152.4,
153.5, 161.5, 168.0; HRMS (m/z): 266.0232 (M + H).+
1
Acknowledgments. The authors would like to express sincere
thanks to the University Grant Commission (UGC), New Delhi,
India, for providing the financial assistance. The Department of
Chemistry, University of Pune and SAIF, Panjab University,
Chandigarh, India, are also acknowledged for spectral analysis.
4-(4-Hydroxy-3-methoxybenzylidene)-3-(chloromethyl)isoxazol-
5(4H)-one (Table 3, entry 5f). mp 184–186 °C; IR (KBr) 3350,
1748, 1555, 1451, 1418, 1174, 1079, 930 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6) δ 3.88 (s, 3H, H3C–O), 4.77 (s, 2H, Cl-
CH2-isoxazol), 6.95 (d, J= 8.8 Hz, 1H, Ar-H), 7.80 (dd, J= 8.8 and
2 Hz, 1H, Ar-H), 7.90 (s, 1H, ¼CH), 8.55 (d, J= 2 Hz, 1H, Ar-H)
10.83 (bs, 1H, Ar-OH); 13C NMR (100 MHz, DMSO-d6) δ 34.9,
55.5, 110.0, 115.8, 116.5, 124.9, 132.5, 147.5, 152.7, 154.7, 161.3,
168.5; HRMS (m/z): 268.0377 (M + H)+.
REFERENCES AND NOTES
[1] Li, C. J. Chem Rev 1993, 93, 2023.
[2] Bigi, F.; Conforti, M. L.; Maggi, R.; Piccinno, A.; Sartori, G.
Green Chem 2000, 2, 101.
[3] Lindstrom, U. M. Chem Rev 2002, 102, 2751.
[4] Otto, S.; Engberts, J. J Org Biomol Chem 2003, 1, 2809.
[5] Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew Chem Int Ed 2005, 44, 3275.
[6] Li, C. J Chem Rev 2005, 105, 3095.
[7] Pirrung, M. C. Chem–Eur J 2006, 12, 1312.
[8] Chanda, A. V.; Fokin, V. Chem Rev 2009, 109, 725.
[9] Butler, R. N.; Coyne, A. G. Chem Rev 2010, 110, 6302.
[10] Simon, M. O.; Li, C. J. Chem Soc Rev 2012, 41, 1415.
[11] Shilaja, M.; Manjula, A.; Vittal Rao, B. Indian J Chem 2011,
50B, 214.
[12] Ishioka, T.; Tanatani, A.; Nagasawa, K.; Hashimoto, Y.
Bioorg Med Chem 2003, 13, 2655.
[13] Deng, B. L.; Hartman, T. L.; Robert, J.; Buckheit, W.;
Pannecouque, C.; Clercq, E. D.; Cushman, M. J Med Chem 2006, 49,
5316.
[14] Laughlin, S. K.; Clark, M. P.; Djung, J. F.; Golebiowski, A.;
Brugel, T. A.; Sabat, M.; Bookland, R. G.; Laufersweiler, M. J.; Van
Rens, R. L.; Townes, J. C.; De, B.; Hsieh, L. C.; Xu, S. C.; Walter, M. J.;
Mekel, M. J.; Janusz, J. A. Bioorg Med Chem Lett 2005, 15, 2399.
[15] Flores, A. F. C.; Zanatta, N.; Rosa, A.; Brondani, S.
Tetrahedron Lett 2002, 43, 5005.
[16] Singh, V.; Saxena, R.; Batra, S. J Org Chem 2005, 70, 353.
[17] Renard, D.; Rezaei, H.; Zard, S. Z. Synlett 2002, 8, 1257.
[18] Alias, R.; Andreu, M. J.; Blesa, M. A.; Cerdan, S.; Franco, J.
J Org Chem 2008, 73, 5890.
[19] Cheng, Q. F.; Liu, X. Y.; Wang, Q. F.; Liu, L. S.; Liu, W. J.;
Lin, Q.; Yang, X. J. Chin J Org Chem 2009, 29, 1267.
[20] Zhang, X. Z.; Zhan, Y. Z.; Chen, D.; Wang, F.; Wang L. Y.
Dyes Pigments 2012, 93, 1408.
[21] Knowles, A. M.; Lawson, A. J Chem Soc, Perkin Trans 1
1972, 1240.
[22] Cook, D. C.; Lawson, A. J Chem Soc, Perkin Trans 1 1974,
1112.
[23] Lo Vecchio, G.; Grassi, G.; Risitano, F.; Foti, F. Tetrahedron
Lett 1973, 39, 3777.
[24] Clerici, F.; Erba, E.; Mornatti, P.; Trimarco, P. Chem Ber
1989, 122, 295.
[25] Cocivera, M.; Emo, A.; Chen, H. E.; Vaish, S. J Am Chem Soc
1976, 98, 7362.
[26] Villemin, D.; Martin, B.; Garrigues, B. Synth Commun 1993,
23, 2251.
4-(4-(Dimethylamino)benzylidene)-3-(chloromethyl)isoxazol-
5(4H)-one (Table 3, entry 5g).
mp 178–180 °C; IR (KBr)
1734, 1589, 1530, 1429, 1180, 1096, 870 cmꢀ1
;
1H NMR
(400 MHz, DMSO-d6) δ 3.19 (s, 6H, (H3C)2 N-), 4.72 (s, 2H,
Cl-CH2-isoxazol), 6.83 (d, J = 8.2 Hz, 2H, Ar-H), 7.72 (s, 1H,
¼CH), 8.46 (d, J = 8.2 Hz, 2H, Ar-H); 13C NMR (100 MHz,
DMSO-d6) δ 35.2, 39.3, 105.4, 111.5, 121.0, 138.0, 150.8,
154.6, 161.1, 169.4; HRMS (m/z): 265.0717 (M + H).+
N-(4-((3-(Chloromethyl)-5-oxoisoxazol-4(5H)-ylidene)methyl)
phenyl)acetamide (Table 3, entry 5 h).
mp 182–184 °C; IR
(KBr) 3333, 3196, 1735, 1600, 1512, 1105, 1010, 956cmꢀ1; H
NMR (300 MHz, CDCl3) δ 2.26 (s, 3H, H3CCO), 4.56 (s, 2H,
Cl-CH2-isoxazol), 7.45 (d, J = 8.8Hz, 2H, Ar-H), 7.54 (bs, 1H,
NH), 7.72 (s, 1H, ¼CH), 8.45 (d, J = 8.8 Hz, 2H, Ar-H); 13C
NMR (75 MHz, CDCl3) δ 29.7, 35.1, 113.6, 115.2, 125.1, 137.1,
151.4, 160.9, 165.7, 169.0; HRMS (m/z): 279.0536 (M + H).+
4-(4-Methylbenzylidene)-3-(chloromethyl)isoxazol-5(4H)-one
1
(Table 3, entry 5i).
mp 178–180 °C; IR (KBr) 1741, 1593,
1522, 1435, 1188, 1091, 877 cmꢀ1;1H NMR (300 MHz, CDCl3)
δ 2.47 (s, 3H, H3C-Ar), 4.56 (s, 2H, Cl-CH2-isoxazol), 7.35
(d, J = 8.2 Hz, 2H, Ar-H), 7.72 (s, 1H, ¼CH), 8.32
(d, J = 8.2 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3) δ 22.3,
35.1, 118.1, 128.8, 129.9, 134.9, 145.8, 150.4, 161.7, 236.0;
MS (m/z): 236.0493 (M + H)+.
4-Benzylidene-3-(chloromethyl)isoxazol-5(4H)-one (Table 3,
entry 5j). mp 184–186 °C; IR (KBr) 1761, 1601, 1552, 1323,
1170, 1085, 922, cmꢀ1 1H NMR (300 MHz, CDCl3) δ 4.50
;
(s, 2H, Cl-CH2-isoxazol), 7.18–7.28 (m, 3H, Ar-H), 7.32 (s, 1H,
¼CH), 7.70 (m, 2H, Ar-H); 13C NMR (75 MHz, CDCl3) δ 34.6,
125.2, 126.8, 128.9, 129.4, 135.1, 151.6, 166.5, 169.0; HRMS
(m/z): 221.0244 (M + H)+.
4-((E)-3-Phenylallylidene)-3-(chloromethyl)isoxazol-5(4H)-
one (Table 3, entry 5k).
mp 186–188 °C; IR (KBr) 1757,
1599, 1546, 1315, 1176, 1096, 868 cmꢀ1; H NMR (300 MHz,
CDCl3) δ 4.52 (s, 2H, Cl-CH2-isoxazol) 7.40 (d, J = 15.8 Hz,
1H, ¼CH), 7.44 (m, 3H, Ar-H), 7.61 (d, J = 15.8 Hz, 1H,
¼CH), 7.66–7.69 (m, 2H, Ar-H), 8.33 (dd, J = 15.8 and
15.8 Hz, 1H, ¼CH); 13C NMR (75 MHz, CDCl3) δ 34.8,
113.6, 121.8, 128.3, 128,9, 131.6, 134.7, 150.7, 153.3, 159.8,
168.0; HRMS (m/z): 248.0465 (M + H)+.
1
[27] Zhang, Y. Q.; Ma, J. J.; Wang, C.; Li, J. C.; Zhang, D. N.;
Zang, X. H.; Li, J. J. Chin J Org Chem 2008, 28, 141.
[28] Liu, Q.; Zhang, Y. Z. Bull Korean Chem Soc 2011, 32, 3559.
[29] Liu, Q.; Wu, R. T. J Chem Res 2011, 10, 598.
[30] Liu, Q.; Hou, X. Phosphorus Sulfur Silicon Relat Elem 2012,
187, 448.
4-((1H-Indol-3-yl)methylene)-3-(chloromethyl)isoxazol-5(4H)-
one (Table 3, entry 5l). mp 240–242 °C; IR(KBr) 1757, 1599,
;
1546, 1315, 1176, 1096, 868cmꢀ1 1H NMR (300 MHz,
DMSO-d6) δ 5.01 (s, 2H, Cl-CH2-isoxazol), 7.37–7.39 (m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Efficient Synthesis of 4-Arylmethylidene-3-substituted-Isoxazol-5(4H)-ones in
Aqueous Medium
[31] Kiyani, H. Org Chem Indian J 2013, 9, 97.
[32] Kiyani, H.; Ghorbani, F. Open J Org Chem 2013, 1, 5.
[33] Kiyani, H.; Ghorbani, F. Res Chem Intermed 2013. DOI:
10.1007/s11164-013-1411-x
[41] Chavan, A. P. J Chem Res 2006, 3, 179.
[42] Chavan, A. P. J Kor Chem Soc 2009, 53, 415.
[43] Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S. G.;
Kozikowski A. P. J Med Chem 2009, 52, 2109.
[34] Kiyani, H.; Ghorbani, F. Elixir Org Chem 2013, 58A, 14948.
[35] Kiyani, H.; Ghorbani, F. Heterocycl Lett 2013, 3, 359.
[36] Kiyani, H.; Ghorbani, F. Heterocycl Lett 2013, 3, 145.
[37] Zhang, Y. Q.; Wang, C.; Zhang, M. Y.; Cui, P. L.; Li, Y. M.;
Zhou, X.; Li J. C. Chin J Org Chem 2008, 28, 914.
[44] Mao, J.; Yuan, H.; Wang, Y.; Wan, B.; Pieroni, M.; Huang, Q.;
van Breemen, R. B.; Kozikowski, A. P.; Franzblau, S. G. J Med Chem
2009, 52, 6966.
[45] Lilienkampf, A.; Pieroni, M.; Wan, B.; Wang, Y.; Franzblau,
S. G.; Kozikowski, A. P. J Med Chem 2010, 53, 678.
[46] Pieroni, M.; Lilienkampf, A. A.; Wan, B.; Wang, Y.;
Franzblau, S. G.; Kozikowski, A. P. J Med Chem 2009, 52, 6287.
[47] Huang, Q.; Mao, J.; Wan, B.; Wang, Y.; Brun, R.; Franzblau,
S. G.; Kozikowski, A. P. J Med Chem 2009, 52, 6757.
[38] Cheng, Q. F.; Liu, X. Y.; Wang, Q. F.; Liu, L. S.; Liu, W. J.;
Lin, Q.; Yang, X. J Chin J OrgChem 2009, 29, 1267.
[39] Saikh, F.; Das, J.; Ghosh, S. Tetrahedron Lett 2013, 54, 4679.
[40] Gholap, A. R.; Chavan, A. P. J Chem Res 2003, 6, 374.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet